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Chapter 33 : Antibiotic Biosynthesis: Some Thoughts on “Why?” and “How?”

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Abstract:

Antibiotics are synthesized by dedicated gene products; they are anything but accidents. All the structural genes required for tylosin biosynthesis are probably present in the cluster, but additional regulatory genes might well be located elsewhere in the genome. Antibiotic-biosynthetic gene clusters commonly include ‘‘pathway-specific’’ regulators. These typically encode transcriptional activators that turn on the structural genes for antibiotic production. Antibiotic-producing organisms are typically resistant to their own toxic metabolite(s), and some of the strategies employed for self-protection are discussed below and elsewhere. Such resistance is usually quite specific for the avoidance of suicide; across-the-board resistance is not common. The fungus that produces penicillin is not faced with any particular problem as a result of doing so, since fungal cell walls do not contain peptidoglycan. On the other hand, actinomycetes that produce antibacterial compounds pose an interesting challenge for themselves. Such strains can adopt either of two resistance strategies in order to avoid suicide. Studies with puromycin and chloramphenicol revealed that peptidyltransferase activity has to do with the larger ribosomal subunit, whereas tetracycline blocked aminoacyl-tRNA binding to the ribosome mRNA complex from a site on the smaller subparticle. The convergence of these various approaches will reveal in molecular detail how antibiotics block conformational transitions that underlie ribosomal function. The ribosome continues to be a focus for the application of ground-breaking methodology to biological systems, and enigmatic small molecules still contribute to our enlightenment.

Citation: Cundliffe E. 2000. Antibiotic Biosynthesis: Some Thoughts on “Why?” and “How?”, p 409-418. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch33

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Figures

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Figure 1

Structures of tylactone and tylosin.

Citation: Cundliffe E. 2000. Antibiotic Biosynthesis: Some Thoughts on “Why?” and “How?”, p 409-418. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch33
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Image of Figure 2
Figure 2

Tylosin-biosynthetic gene cluster of (not drawn to scale). The total size of the cluster is ~85 kb, of which the five genes occupy ˜41 kb. The data are taken from ; and . The genes were sequenced at Lilly Research Laboratories (Indianapolis, Ind.) (GenBank accession no. U78289) but not formally published. Data relating to open reading frames 8 to 10 also originated at Lilly (DeHoff and Rosteck, personal communication).

Citation: Cundliffe E. 2000. Antibiotic Biosynthesis: Some Thoughts on “Why?” and “How?”, p 409-418. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch33
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Figure 3

Biosynthesis of the tylosin sugars. During assembly of the tylosin molecule, mycaminose is the first sugar added to the polyketide ring, followed, in a preferred but not obligatory order, by deoxyallose and mycarose. After addition to the ring, the deoxyallose moiety is converted to mycinose via bis Omethylation, involving sequential action of the and products.

Citation: Cundliffe E. 2000. Antibiotic Biosynthesis: Some Thoughts on “Why?” and “How?”, p 409-418. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch33
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Image of Figure 4
Figure 4

Structure of the γ-butyrolactone signal molecule, Afactor.

Citation: Cundliffe E. 2000. Antibiotic Biosynthesis: Some Thoughts on “Why?” and “How?”, p 409-418. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch33
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References

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1. Baltz, R. H.,, and E. T. Seno. 1988. Genetics of Streptomyces fradiae and tylosin biosynthesis. Annu. Rev. Microbiol. 42: 547 574.
2. Bate, N.,, and E. Cundliffe. 1999. The mycinose-biosynthetic genes of Streptomyces fradiae, producer of tylosin. J. Ind. Microbiol. Biotechnol. 23: 118 122.
3. Bate, N.,, A. R. Butler,, A. R. Gandecha,, and E. Cundliffe. 1999. Multiple regulatory genes in the tylosin biosynthetic cluster of Streptomyces fradiae. Chem. Biol. 6: 617 624.
4. Bate, N.,, A. R. Butler,, I. P. Smith,, and E. Cundliffe. 2000. The mycarose-biosynthetic genes of Streptomyces fradiae, producer of tylosin. Microbiology 146: 139 146.
5. Chater, K. F.,, and M. J. Bibb,. 1997. Regulation of bacterial antibiotic production, p. 59 105. In H. Kleinkauf, and H. von Dören (ed.), Biotechnology, Vol. 7. Products of Secondary Metabolism. VCH, Weinheim, Germany.
6. Chiu, M. L.,, M. Folcher,, P. Griffin,, T. Holt,, T. Klatt,, and C. J. Thompson. 1996 Characterization of the covalent binding of thiostrepton to a thiostrepton-induced protein from Streptomyces lividans. Biochemistry 35: 2332 2341.
7. Cundliffe, E. 1989. How antibiotic-producing organisms avoid suicide. Annu. Rev. Microbiol. 43: 207 233.
8. Cundliffe, E., 1990. Recognition sites for antibiotics within rRNA, p. 479 490. In W. E. Hill, , A. Dahlberg, , R. A. Garrett, , P. B. Moore, , D. Schlessinger, , and J. R. Warner (ed.) , The Ribosome: Structure, Function, and Evolution. American Society for Microbiology, Washington, D.C.
9. Davies, J. 1990. What are antibiotics? Archaic functions for modern activities. Mol. Microbiol. 4: 1227 1232.
10. DeHoff, B. S., , and P. R. Rosteck, Jr. Personal communication.
11. Distler, J., , A. Ebert, , K. Mansouri, , K. Pissowotzki, , M. Stockmann, , and W. Piepersberg. 1987. Gene cluster for streptomycin biosynthesis in Streptomyces griseus: nucleotide sequence of three genes and analysis of transcriptional activity. Nucleic Acids Res. 15: 8041 8056.
12. Fishman, S. E.,, K. Cox,, J. L. Larson,, P. A. Reynolds,, E. T. Seno,, W.-K. Yeh,, R. Van Frank,, and C. L. Hershberger. 1987. Cloning genes for the biosynthesis of a macrolide antibiotic. Proc. Natl. Acad. Sci. USA 84: 8248 8252.
13. Fröhlich, K.-U.,, M. Wiedmann,, F. Lottspeich,, and D. Mecke. 1989. Substitution of a pentalenolactone-sensitive glyceraldehyde- 3-phosphate dehydrogenase by a genetically distinct resistant isoform accompanies pentalenolactone production in Streptomyces arenae. J. Bacteriol. 171: 6696 6702.
14. Gale, E. F., 1966. The object of the exercise, p. 1 21. In B. A. Newton, and P. E. Reynolds (ed.), Biochemical Studies of Antimicrobial Drugs. Cambridge University Press, Cambridge, United Kingdom.
15. Gale, E. F.,, E. Cundliffe,, P. E. Reynolds,, M. H. Richmond,, and M. J. Waring. 1981. The Molecular Basis of Antibiotic Action, 2nd ed. John Wiley and Sons, London, United Kingdom.
16. Gandecha, A. R.,, and E. Cundliffe. 1996. Molecular analysis of tlrD, an MLS resistance determinant from the tylosin producer, Streptomyces fradiae. Gene 180: 173 176.
17. Gandecha, A. R.,, S. L. Large,, and E. Cundliffe. 1997. Analysis of four tylosin biosynthetic genes from the tylLM region of the Streptomyces fradiae genome. Gene 184: 197 203.
18. Hancock, R. E. W.,, and D. S. Chapple. 1999. Peptide antibiotics. Antimicrob. Agents Chemother. 43: 1317 1323.
19. Horinouchi, S.,, and T. Beppu. 1994. A-factor as a microbial hormone that controls cellular differentiation and secondary metabolism in Streptomyces griseus. Mol. Microbiol. 12: 859 864.
20. Kelemen, G. H.,, M. Zalacain,, E. Culebras,, E. T. Seno,, and E. Cundliffe. 1994. Transcriptional attenuation control of the tylosin resistance gene, tlrA, in Streptomyces fradiae. Mol. Microbiol. 14: 833 842.
21. Kirillov, S.,, B. T. Porse,, B. Vester,, P. Wolley,, and R. A. Garrett. 1997. Movement of the 3′-end of tRNA through the peptidyl transferase centre and its inhibition by antibiotics. FEBS Lett. 406: 223 233.
22. Lehrer, R. I.,, and T. Ganz. 1996. Endogenous vertebrate antibiotics— defensins, protegrins and other cysteine-rich antimicrobial peptides. Ann. N. Y. Acad. Sci. 797: 228 239.
23. Mansouri, K.,, and W. Piepersberg. 1991. Genetics of streptomycin production in Streptomyces griseus: nucleotide sequence of five genes, strFGHIK, including a phosphatase gene. Mol. Gen. Genet. 228: 459 469.
24. Menzel, R.,, and M. Gellert. 1983. Regulation of the genes for E. coli DNA gyrase: homeostatic control of DNA supercoiling. Cell 34: 105 113.
25. Merson-Davies, L. A.,, and E. Cundliffe. 1994. Analysis of five tylosin biosynthetic genes from the tylIBA region of the Streptomyces fradiae genome. Mol. Microbiol. 13: 349 355.
26. Mosher, R. H.,, D. J. Camp,, K. Yang,, M. P. Brown,, W. V. Shaw,, and L. C. Vining. 1995. Inactivation of chloramphenicol by Ophosphorylation. A novel resistance mechanism in Streptomyces venezuelae ISP5230, a chloramphenicol producer. J. Biol. Chem. 270: 27000 27006.
27. Murakami, T.,, T. G. Holt,, and C. J. Thompson. 1989. Thiostrepton- induced gene expression in Streptomyces lividans. J. Bacteriol. 171: 1459 1466.
28. Reece, R. J.,, and A. Maxwell. 1991. DNA gyrase: structure and function. Crit. Rev. Biochem. Mol. Biol. 26: 335 375.
29. Rosteck, P. R., Jr.,, P. A. Reynolds,, and C. L. Hershberger. 1991. Homology between proteins controlling Streptomyces fradiae tylosin resistance and ATP-binding transport. Gene 102: 27 32.
30. Thiara, A. S.,, and E. Cundliffe. 1988. Cloning and characterization of a DNA gyrase B gene from Streptomyces sphaeroides that confers resistance to novobiocin. EMBO J. 7: 2255 2259.
31. Thiara, A. S.,, and E. Cundliffe. 1989. Interplay of novobiocinresistant and -sensitive DNA gyrase activities in self-protection of the novobiocin producer, Streptomyces sphaeroides. Gene 81: 65 72.
32. Thompson, J.,, F. J. Schmidt,, and E. Cundliffe. 1982. Site of action of a ribosomal RNA methylase conferring resistance to thiostrepton. J. Biol. Chem. 257: 7915 7917.
33. Vilches, C.,, C. Hernandez,, C. Mendez,, and J. A. Salas. 1992. Role of glycosylation and deglycosylation in biosynthesis of and resistance to oleandomycin in the producer organism, Streptomyces antibioticus. J. Bacteriol. 174: 161 165.
34. Vining, L. C. 1990. Functions of secondary metabolites. Annu. Rev. Microbiol. 44: 395 427.
35. Walker, J. B.,, and M. Skorvaga. 1973. Phosphorylation of streptomycin and dihydrostreptomycin by Streptomyces. J. Biol. Chem. 248: 2435 2440.
36. Weisblum, B. 1998. Macrolide resistance. Drug Res. Updates 1: 29 41.
37. Wietzorrek, A.,, and M. Bibb. 1997. A novel family of proteins that regulates antibiotic production in streptomycetes appears to contain an OmpR-like DNA-binding fold. Mol. Microbiol. 25: 1177 1184.
38. Wilson, V. T. W.,, and E. Cundliffe. 1998. Characterization and targeted disruption of a glycosyltransferase gene in the tylosin producer, Streptomyces fradiae. Gene 214:95-100.
39. Wilson, V. T. W., , and E. Cundliffe. 1999. Molecular analysis of tlrB, an antibiotic-resistance gene from tylosin-producing Streptomyces fradiae, and discovery of a novel resistance mechanism. J. Antibiot. 52: 288 296.
40. Zalacain, M.,, and E. Cundliffe. 1989. Methylation of 23S rRNA caused by tlrA ( ermSF), a tylosin resistance determinant from Streptomyces fradiae. J. Bacteriol. 171: 4254 4260.
41. Zalacain, M.,, and E. Cundliffe. 1991. Cloning of tlrD, a fourth resistance gene, from the tylosin producer, Streptomyces fradiae. Gene 97: 137 142.

Tables

Generic image for table
Table 1

Antibiotic-inactivating enzymes in organisms producing ribosome inhibitors

Citation: Cundliffe E. 2000. Antibiotic Biosynthesis: Some Thoughts on “Why?” and “How?”, p 409-418. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch33
Generic image for table
Table 2

Resistance due to methylation of rRNA in antibiotic producers

Citation: Cundliffe E. 2000. Antibiotic Biosynthesis: Some Thoughts on “Why?” and “How?”, p 409-418. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch33
Generic image for table
Table 3

Antibiotic resistance due to altered properties of nonribosomal drug targets

Citation: Cundliffe E. 2000. Antibiotic Biosynthesis: Some Thoughts on “Why?” and “How?”, p 409-418. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch33

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